Principal Investigator/Program Director (Last, first, middle): KO, Tien C., MD PROJECT SUMMARY Chronic alcohol consumption is the most common cause of chronic pancreatitis (CP), a devastating fibro-inflammatory disease of the pancreas with no effective therapy. The unmet need for CP therapy is largely due to fundamental gaps in our understanding of the complex mechanisms that regulate CP progression. Transforming growth factor (TGF)-? and bone morphogenetic protein (BMP), members of the TGF-? superfamily, play pro- and anti-fibrogenic roles, respectively, in CP. Gremlin1 (Grem1), a prominent endogenous BMP antagonist, is elevated in CP. Grem1 can be experimentally induced by TGF-?, alcohol metabolite and cerulein in vitro in pancreatic stellate cells (PSCs), the key effector cells in CP. Grem1 can block BMP signaling in these cells. Thus, a balance between BMP and TGF-? signaling through Grem1 regulation may dictate CP progression. The objective of this proposal is to understand the protective role of BMP signaling during the disease progression. This study will take both in vivo approach by employing two alcohol (A)-induced CP mouse models in conditional BMP receptor and Grem1 knockout mice, and in vitro approach by using PSCs for mechanistic studies. Human pancreatic cells and tissue samples will be utilized for validating key findings from mouse studies. Two Specific Aims will be pursued. Specific Aim 1 determines the anti-fibrogenic effects of BMP signaling in alcohol-induced chronic pancreatitis by evaluating whether blocking BMP signaling exacerbates CP and how BMP signaling opposes TGF-? signaling. Specific Aim 2 investigates the mechanisms of suppression of BMP signaling in alcohol-induced chronic pancreatitis by examining whether Grem1 knockout ameliorates CP, how alcohol enhances Grem1 expression, and whether Grem1 levels correlate with TGF-? and BMP signaling in human CP. The proposed study is expected to provide mechanistic insights into a novel protective key signaling pathway in CP, which will lead to a better understanding of the disease progression and innovative approaches to CP therapy. 1